Sjogren's syndrome is a chronic inflammatory autoimmune disease that mainly involves exocrine glands. Its inflammatory response is mainly manifested in epithelial cells of exocrine glands. Clinically, in addition to the impaired function of salivary glands and lacrimal glands, i.e., dry mouth and dry eyes, there are other exocrine glands and other organs outside the gland and the symptoms of multiple system damage. The patient's serum contains multiple autoantibodies and hyperimmune globulins. The disease is divided into primary and secondary types. Primary Sjogren's syndrome is a global disease with a prevalence of 0.3% to 0.7% in the Chinese population. More than 90% of the patients is female, the ratio of male to female is 1:9 to 1:20, and the age of onset is mostly 40-50 years old. Since the earliest description of Sjogren's syndrome at the end of the 19th century, the research history has been more than a hundred years. Although its pathogenesis has not yet been fully elucidated, some progress has been made since the 1990s. With the development of immunology and molecular biology techniques, the pathogenesis of SS has been studied and the etiology may be related to factors such as heredity, immunity, endocrinology, and viral infection. At present, consensus has been basically reached. Most scholars believe that SS has genetic susceptibility. On this basis, local non-specific inflammation induces the expression of cytokines IFN-γ and TNF-α, triggering a series of immune responses (Ann Rheum Dis, 2003), 62(4):359-62. Clin Rev Allergy Immunol, 2007, 32(3):252-64). Due to the disorder of the immune regulation mechanism, the inflammation is persistently chronic and damages the exocrine glands. Therefore, the pathological changes are mainly the infiltration of lymphocytes and plasma cells into the glandular tissue and cause progressive destruction, resulting in reduced secretion of saliva and tears, and in turn the dry mouth and eyes symptom.
There is no safe and effective treatment for this disease at present. Some measures are mainly taken to improve symptoms, control and delay the progress of tissue damage caused by the immune response and secondary infections. Non-steroidal anti-inflammatory drugs (NSAIDS) are mainly used for the treatment of SS muscles, joint pain, mild serositis and fever and other symptoms, generally have a quicker effect and are effective for several days after administration. However, these treatments are limited to relieve symptoms. The side effects include digestive tract reactions (even bleeding), kidney damage, and myelosuppression. They can also cause liver damage, occasional skin rashes, cytopenia, or pancreatitis. When patients with Sjogren's syndrome have visceral multiple system damage, such as nervous system, blood system, severe interstitial lung disease, vasculitis, hepatic damage, myositis, etc., it is generally necessary to use glucocorticoids for treatment. In critical condition, hormone shock treatment can be used. It should be noted that the use of long-term glucocorticoids can produce the following side effects, such as: iatrogenic adrenocortical hyperactivity, induction and aggravation of infection, induction and aggravation of peptic ulcer, osteoporosis, aseptic bone necrosis. For the patient with rapid progress of the disease, can be administrated in combination with immunosuppressive agents, such as cyclophosphamide, azathioprine and so on.
Although the research history of SS has exceeded 100 years, its etiology and pathogenesis remain unclear. Immunity, genetics, environment, infection, abnormal neuromodulation and other factors may be related to the onset of SS. Studies have shown (Journal of Autoimmunity, 2001, 17:141-153) that there is an extensive and close relationship between cytokines and SS, which plays an important role in the pathogenesis of SS. For example, interferon can both inhibit the growth and differentiation of salivary gland epithelial cells (SGEC) and induce SGEC isolation and apoptosis (J. Immunol, 2000, 164:1277-1285). Tumor necrosis factor (TNF-α) promotes the lysis of glandular cells and alters the adhesion properties of endothelial cells (Adv Exp Med Biol, 1998, 438:909-915). Interleukins regulate cell growth and differentiation in SS exocrine tissue lesions, affect the behavior and characteristics of many cells, participate in inflammatory reactions, and modulate immune responses (Arthritis Rheum, 1997, 40: 987-990). Fox et al. (Cur Opi Rheum, 2000, 12:391-398) found that the levels of IL-1α,6 and TNF-α mRNA produced by SS patient's SGEC are 40-fold higher than those of normal SGEC. The levels of IL-1β, IL-6, IL-10, TNF-α and IFN-γ in salivary glands of SS patients were increased, which can be detected by ELISA (Lab Invest. 1999. 12:1719-1726). Therefore, cytokine-mediated inflammation is an important pathogenesis of SS.
Nuclear factor-κB (NF-κB) is a DNA-binding protein that regulates gene expression. It regulates the expression of many important cytokines, adhesion molecules, and chemokine genes, and participates in various physiological and pathological processes of the body, the most important of which are immune and inflammatory reactions. NF-κB has been shown to be a very important type of transcription factor that is ubiquitous in the course of inflammation and immune response. NF-κB is a rapidly-reacting transcription factor and play a role through the expression of inflammatory mediators (IL-1β, IL-6, IL-10, TNF-α, etc.), adhesion molecules, and enzymes in an inflammatory reaction. In the course of inflammation, NF-κB is involved in the activation of macrophages and leukocytes, and controls the gene expression of many cytokines, inflammatory protein and proinflammatory cytokines. Loss of control in this regulatory process will lead to amplification of the inflammatory response and tissue damage. Studies have shown (Arthritis Res Ther. 2012 Mar. 14; 14(2):R64) that the activation of toll-like receptor 2 (TLR 2) can induce IL-23/IL-17 expression through NF-κB, which process is closely related to the formation of SS. Lisi Si et al. also found that a decrease in the expression of nuclear factor κB inhibitor α (IκBα) can upregulate the NF-κB pathway and increase the production of SS-related cytokines and inflammation, leading to the occurrence of SS (Lisi et al., Pathology. 2012 October; 44(6):557-61).
Oxidative stress (OS) refers to the imbalance between oxidation and antioxidation in the body. Excessive production of highly reactive molecules such as reactive oxygen species (ROS) and reactive nitrogen radicals (RNS) results in the oxidation exceeding oxide removal, leading to neutrophil inflammatory infiltration and tissue damage. ROS includes superoxide anion, hydroxyl radical and hydrogen peroxide; RNS includes nitric oxide, nitrogen dioxide and peroxynitrite. Representative biomarkers of oxidative stress are 8-hydroxydeoxyguanosine (8-OHdG), thioredoxin (TRX).
8-OHdG is a sensitive marker of oxidative stress DNA damage. It is reported that 8-OHdG was found to increase in the saliva of SS patients but not in other patients with salivary gland dysfunction and normal individuals (Ryo et al., Pathobiology. 2006; 73(5):252-60). In SS patients, both protein oxidation markers PC (protein carbonyl) and APOO (Advanced Oxidation Protein Product) were increased (Free Radic Res. 2012 February; 46(2):141-6). Some researchers compared oxidative stress levels in patients with dry eyes and those without dry eye in conjunctival epithelial cells in dry eye models and SS patients through tear test, fluorescein clearance, BUT scores and OSDI scores (Graefes Arch Clin Exp Ophthalmol. 2015 March; 253(3):425-30). Oxidative stress in patients with dry eyes was found to be higher than in those without dry eyes. In SS NOD (NOD.B10.Sn-H2) mouse model, pancreatic exocrine cells and artificially cultured human salivary gland cells, the antioxidant epigallocatechin has increased defensive antioxidant capacity through the mitogen-activated protein kinase signaling pathway (Autoimmunity. 2014 May; 47(3):177-84). The above documents all show that oxidative stress participates in the destruction of salivary gland tissue in SS and participates in the pathological process of SS.
Recent studies (Pagano et al., Free Radic Res. 2013 February; 47(2):71-3) have found that in plasma of SS patients, protein oxidation, myeloperoxidase activity, TNF-α, nitrotyrosine, and the level of glutathione changed significantly. In SS patients, changes in mitochondria of the cells and mitochondrial dysfunction result in the oxidative stress-related disorders, involving in the formation of oxidative stress.
In addition, it has been reported that thioredoxin (TRX) exerts a protective effect against salivary gland oxidative stress tissue damage in SS (J Rheumatol. 2007 October; 34(10):2035-43). In SS patients, a large amount of 8-OHdG and TRX were produced in salivary duct cells, and TRX was significantly negatively correlated with salivary flow rate. In addition, after acting on human salivary gland cells, TRX significantly inhibited IFN-γ-induced IL-6 expression and Fas-regulated apoptosis. TRX is an important antioxidant in cells, and even alone can eliminate the singlet oxygen and hydroxyl radicals. The expression of IL-6 and Fas-regulated apoptosis are the pathological process of typical inflammatory responses. Antioxidants inhibit the inflammatory response of inflammatory factors and apoptosis, thereby protecting the salivary glands of SS patients from tissue damage caused by inflammation. This also shows that oxidative stress can cause tissue damage by triggering the inflammatory response of the gland and thus participate in the pathogenesis of SS.
In summary, antioxidants can eliminate oxidative stress and inhibit the inflammatory damage caused by oxidative stress in the pathological process of SS, thereby preventing the pathological process of SS. Among others, the inflammatory injury process may be performed by activating the NF-κB pathway. Therefore, anti-oxidation may become a new SS treatment, and finding the right antioxidant may be an important direction for future research and development.
Common antioxidants are superoxide dismutase, catalase, thioredoxin, N-acetylcysteine, ergothioneine, vitamin C, vitamin D, vitamin E, glutathione, melatonin, alpha-lipoic acid, carotenoids, trace elements copper, zinc, selenium (Se) and so on.
Vitamin d has a wide range of effects, including inhibition of Th17 cell-mediated autoimmunity (Mol. Cell. Biol. 2011, 31(17):3653). Vitamin D deficiency (VitD) is common in SS patients, especially in female SS patients, which have a high risk of VitD deficiency (Erten et al., Int J Rheum Dis. 2015 January; 18(1):70-5). Low vitamin D levels in patients with SS may be associated with serious complications such as lymphoma and peripheral neuropathy. Supplementation of Vitamin D may be an additional tool for optimal treatment of SS. Vitamin D may play a role in pathological processes and disease expression of neuropathy in SS patients and may be used to monitor and treat this complication. There is a clear correlation between vitamin D deficiency and severe SS complications. It is recommended that vitamin D supplementation be given to every SS patient (BMC Med. 2013 Apr. 4; 11:93). However, vitamin D itself has no biological activity and needs to be further metabolized in the body to be hydroxylated into active vitamin D (1,25-Dihydroxyvitamin D3). Its clinical application dose is relatively large. In order to ensure efficacy, it is sometimes necessary to inject dosing.
N-acetylcysteine (NAC) is a precursor of glutathione synthesis in vivo and is an important antioxidant. In a study, 26 patients with primary or secondary Sjogren's syndrome are selected to undergo a randomized, double-blind trial. The experimental and control groups were treated with N-acetylcysteine (NAC) and placebo for 4 days, respectively. As a result, it was found that after treatment with NAC, the pain, sensation of the eyes, bad breath and daytime thirst are improved. This indicates that NAC has a true therapeutic effect on the ocular symptoms of SS patients and deserves further investigation (Walters et al., Scand J Rheumatol Suppl. 1986; 61:253-8). However, the clinical application of NAC has obvious deficiencies: NAC is not stable in vivo and requires a large dose to ensure efficacy. At the same time, NAC is an acidic substance that needs to be taken up to 1.2 grams per day in human trials (Altem Med Rev. 2000 October; 5(5):467-71), which dose may cause gastrointestinal symptoms in some patients. Moreover, according to the 2010 Pharmacopoeia of the People's Republic of China, NAC is a well-known TB drug and has many other adverse effects, including severe poisoning.
Therefore, it is necessary to find more stable, safe, efficient pharmaceutical active substances, or drug combinations for the treatment of Sjogren's syndrome.